The rupture of arterial aneurysms is an important cause of serious disability and death. For example, about 1.3% of the males over 50 years of age in the United Kingdom and in Scandinavia die of rupture of aortic aneurysms. The incidence is lower in women, probably because the earlier development of atherosclerosis in males predisposes the arteries to dilatation and rupture. Cerebral aneurysms are also a frequent cause of morbidity and mortality. The incidence of ruptured cerebral aneurysms is about 4 per 100,000 per year. It is estimated that up to 20% of the general population harbors such cerebral aneurysms. The disease is a devastating one in that as many as 25% of patients who suffer from rupture of a cerebral aneurysm die during the first day and about half succumb in the first three months.
Because of the dire consequences of vascular aneurysm, detection of persons at risk before aneurysms rupture is needed so these persons can be monitored or preventive surgery can be performed.
Type III collagen is a member of the family of fibrillar collagens and accounts for five to twenty per cent of the collagen present in mammals. The Type III procollagen molecule is formed from three identical pro.alpha.1(III) chains. Each chain contains three separate domains. The N-propeptide domain at one of the chain contains a globular subdomain, a short triple helical subdomain, and finally another short subdomain that forms part of the cleavage site for removal of the N-propeptide. The C-propeptide domain at the other end of the chain is entirely globular. The central, or collagen, domain consists of the .alpha. chains. Each of the three .alpha. chains is coiled into a left-handed helix, and the three helical chains are twisted around each other into a right-handed superhelix. Each .alpha. chain contains about 1,000 amino acid residues, and with the exception of short sequence at the ends of the chains, every third amino acid is glycine. Therefore the molecular formula of an .alpha. chain can be represented as (Gly-X-Y), where X and Y denote amino acids other than glycine. The presence of glycine, the smallest amino acid, in every third position is crucial, since the amino acid in this position occupies a restricted space in which the three helical chains come together in the center of a triple helix. Proline and 4-hydroxyproline frequently occupy the X and Y positions, respectively. Assembly of the procollagen molecule involves a large number of post-translational modifications, which require at least eight specific and several non-specific enzymes. In all, over 100 amino acids in each pro.alpha. chain are modified. In the final conversion of procollagen to collagen, one third of the mass is cleaved from the protein. The Type III procollagen gene (COL3A1) codes for the pro.alpha.1(III) chains which are then modified to form the mature molecule.
Type III collagen is generally found in association with Type I collagen but is particularly abundant in tissues such as aorta. In contrast, it is absent from bone. The function of Type III collagen has not been fully defined, but its essential role is illustrated by the heritable disorder of connective tissue known as Ehlers-Danlos syndrome type IV in which decreased synthesis or synthesis of structurally abnormal Type III procollagen produces aortic aneurysms and rupture of other hollow organs.
Many variants of osteogenesis imperfecta, the Marfan syndrome, the Ehlers-Danlos syndrome and several related disorders have a genetic component involving defects in collagen genes, specifically, Type I and Type III collagen. In these "collagen diseases" mutations in Type I or Type III collagen genes have been found to cause altered forms of these collagens which in turn result in the physical changes in joints, skin and blood vessels characteristic of each disease. The structure of collagen and heritable "collagen diseases" are reviewed in Prockop and Kivirikko, (1984) New England Journal of Medicine 311: 376-386, prockop, (1985) J. Clin. Invest. 75: 783-787, and Prockop (1986) Hospital Practice February 15, 1986.
Pope et al., (1981) The Lancet May 2, 1981, 973-975 analyzed collagen of patients undergoing surgical treatment for intracranial hemorrhage caused by ruptured cerebral aneurysm and found that seven of the twelve patients with cerebral aneurysm examined were deficient in Type III collagen.